Preparation of oxycodone

ABSTRACT

A method of purifying oxycodone or a salt thereof includes the steps of:
         a) preparing a solution including the oxycodone or salt thereof in a solvent, the solution having a pH less than 6, and;   b) maintaining the solution at a temperature of at least 55° C. for a period of at least 1 hour;   wherein the step of maintaining is performed in the absence of hydrogenation reagents.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/586,392, filed Oct. 25, 2006, which is a continuation of U.S. patentapplication Ser. No. 11/234,627, filed Sep. 23, 2005, which claimspriority of British Patent Application No. 0421149.6, filed Sep. 23,2004, the entirety of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a process for preparing oxycodonehaving low levels of impurities. In particular, the process is usefulfor preparing oxycodone with low levels of α,β-unsaturated ketones.

BACKGROUND OF THE INVENTION

Oxycodone is a narcotic analgesic having the structure (I):

Oxycodone can be manufactured from the natural product thebaine (II) bya well-known process as disclosed in U.S. Pat. No. 6,090,943:

Thebaine (II) or a salt thereof is reacted with hydrogen peroxide inisopropanol, water and formic acid, producing 14-hydroxycodeinone (III).The double bond in the 14-hydroxycodeinone (III) is reduced by reactionwith hydrogen in the presence of a Pd/BaSO₄ catalyst, providingoxycodone (I).

SUMMARY OF THE INVENTION

Recently there has been a concern about the presence of α,β-unsaturatedketone impurities in pharmaceutical products. 14-hydroxycodeinone (III)is an α,β-unsaturated ketone, and unsurprisingly, small quantities ofthis compound may be found in oxycodone (I). The present inventors havesought to provide a method for preparing oxycodone having low levels ofimpurities and in particular, low levels of α,β-unsaturated ketoneimpurities, preferably below 10 ppm.

In one aspect, the invention provides a method of purifying oxycodone ora salt thereof, including the steps of:

-   -   a) preparing a solution including the oxycodone or salt thereof        in a solvent, the solution having a pH less than 6, and;    -   b) maintaining the solution at a temperature of at least 55° C.        for a period of at least 1 hour;        wherein the step of maintaining is performed in the absence of        hydrogenation reagents.

In another aspect, the invention provides a method of purifyingoxycodone or a salt thereof, including the steps of:

-   -   a) preparing a solution including the oxycodone or salt thereof        in a solvent, the solution having a pH less than 6, and;    -   b) maintaining the solution at a temperature of at least 55° C.        for a period of at least 1 hour;        wherein the solution includes, after the maintaining step, a        level of 14-hydroxycodeinone that is higher than a level of        14-hydroxycodeinone before the maintaining step.

In yet another aspect, the invention provides crystalline oxycodonehydrochloride including less than 2 ppm of 14-hydroxycodeinone.

The present invention provides a process for preparing oxycodone or anoxycodone salt, wherein the oxycodone or oxycodone salt has low levelsof impurities, comprising the steps of:

-   -   a) preparing a mixture comprising oxycodone and a solvent and        adjusting the pH of the mixture to less than 6; and subsequently    -   b) exposing the mixture to hydrogenation reagents for a period        of at least 1 hour.

The inventors have found that this process surprisingly providesoxycodone with low levels of α,β-unsaturated ketone impurities, i.e.14-hydroxycodeinone at less than 15 ppm. The inventors have found thatin order to achieve low levels of 14-hydroxycodeinone, the pH must beadjusted before the hydrogenation step. Suitably the mixture is heatedafter the pH of the mixture is adjusted, so that the process comprisesthe steps of:

-   -   a) preparing a mixture comprising oxycodone and a solvent,        adjusting the pH of the mixture to less than 6 and heating the        mixture at the temperature of at least 55° C. for a period of at        least 1 hour; and subsequently    -   b) exposing the mixture to hydrogenation reagents for a period        of at least 1 hour.        This process provides oxycodone with very low levels of        α,β-unsaturated ketone impurities, i.e. 14-hydroxycodeinone at        less than 5 ppm.

DETAILED DESCRIPTION OF THE INVENTION

The mixture comprising oxycodone and a solvent can be prepared by anumber of methods. In a first method, oxycodone base or a salt ofoxycodone, prepared and isolated using any of the methods known to thoseskilled in the art, is mixed with a solvent to form the mixture. In asecond method, 14-hydroxycodeinone is hydrogenated in a solvent usingknown hydrogenation reagents, thereby providing a mixture comprisingoxycodone and a solvent. In a third method, a mixture comprisingthebaine and a solvent is subjected to oxidation conditions (e.g.hydrogen peroxide in formic acid and water), followed by hydrogenationconditions, thereby providing a mixture comprising oxycodone and asolvent. Other methods of preparing a mixture comprising oxycodone and asolvent may be known to those skilled in the art.

The pH of the mixture is adjusted to less than 6, suitably less than 5,more suitably less than 3 and preferably about 1. The pH is suitablyadjusted by the addition of a strong acid such as concentratedhydrochloric acid to the mixture. Preferably at least one equivalent ofacid is added to the mixture.

The solvent in the mixture is suitably an organic solvent such asisopropanol, ethanol or SD3A (a 95:5 mixture of ethanol:methanol).Preferably the mixture further comprises water.

After the pH is adjusted, the mixture is suitably heated to atemperature of at least 55° C., preferably at least 60° C. and mostpreferably about 70-75° C. The temperature is suitably not higher thanthe boiling point of the solvent. The mixture is suitably heated for aperiod of at least 1 hour, preferably at least 3 hours and mostpreferably between 5-10 hours.

Suitable hydrogenation reagents are well known to the skilled person andtypically include a hydrogenation catalyst and either hydrogen or ahydrogen transfer reagent, such as sodium hypophosphite. Preferredhydrogenation catalysts are precious metal catalysts such as palladiumor platinum dispersed on a support material such as carbon or bariumsulfate. In a preferred embodiment, a precious metal catalyst is addedto the mixture and hydrogen is passed through the mixture at a pressureof 10 psi or more (162 kPa or more). The hydrogenation step is suitablycarried out at a temperature of at least ambient, preferably at atemperature between room temperature and 70° C. The temperature shouldbe sufficient to dissolve the solids in the mixture, thereby providing asolution. The mixture is exposed to the hydrogenation reagents for atleast 1 hour, suitably at least 2 hours and preferably about 6 hours.

The product of step (b) is a mixture comprising oxycodone and a solvent.Hydrogenation catalysts may be removed by filtering the mixture. Apurified oxycodone salt may be obtained from the mixture by reducing thetemperature, and allowing the salt to crystallise out. For example, ifhydrochloric acid was used in step (a), the hydrochloride salt ofoxycodone will be produced. Alternatively, oxycodone base may beprovided by adding a base such as sodium hydroxide to the mixture andallowing the mixture to cool.

If precious metal catalysts are used in the hydrogenation step, it ispossible that unacceptable levels of the metals will remain in the finalproduct (desirably the heavy metal content of the final product is lessthan 20 ppm). In one embodiment of the present invention, the oxycodoneor oxycodone salt produced in step (b) is subjected to a further processwherein a mixture comprising the oxycodone or oxycodone salt and asolvent is treated with charcoal. Suitably the mixture is heated to atemperature of approx. 60-65° C., the charcoal is added, the mixture isstirred at 60-65° C. for 5 to 10 hours and the hot mixture is filteredto remove the charcoal. Cooling the hot mixture provides the oxycodonesalt or oxycodone. Suitably the weight ratio of oxycodone or oxycodonesalt to charcoal is between 20:1 and 1:1, preferably about 5:1. Thecharcoal is suitably a charcoal such as Darco® G-60 (Norit, USA).

Oxycodone or an oxycodone salt produced according to the process of theinvention has low levels of α,β-unsaturated ketones and isadvantageously incorporated into pharmaceutical products.

EXAMPLES

The following examples are illustrative but not limiting of theinvention.

Preparation of Oxycodone Base: Route A

Thebaine (15.94 g) was added to a 250 ml flask. Water (18 ml) was addedand the mixture was stirred at room temperature. Formic acid (42 ml) wasadded over 3 minutes and then the mixture was cooled in an ice bath.Hydrogen peroxide (30%, 6.7 g) was added and the mixture was stirred for1 hour. The mixture was removed from the ice bath, allowed to warm toroom temperature and then heated to 48° C. for 2 hours. The mixture wastransferred to a hydrogenation bottle. A 5 wt % palladium on carboncatalyst (2 g) was added and hydrogen was passed through the mixture atapproximately 20 psi for 15 hours. The catalyst was removed by passingthe mixture through a pad of celite and rinsing the filtered solid withwater/formic acid (3:1, 8 ml). The mixture was cooled in an ice bath and25% sodium hydroxide (109 ml) was added dropwise over 50 minutes toincrease the pH to 9-10. The mixture was stirred for 1 hour and 15minutes and the solid product was filtered, rinsed with cold water anddried under vacuum pump for 3 hours. The product was oxycodone base(14.152 g, 87.7% yield) and contained 178 ppm of the α,β-unsaturatedketone impurity, 14-hydroxycodeinone.

Preparation of Oxycodone Base: Route B

Thebaine (100.0 g dry weight) was dissolved in 85% formic acid (252.3g). 30% Hydrogen peroxide (43.6 g) was added over a period of about twohours. The mixture was stirred for three hours. Ammonium hydroxidesolution was added to the mixture to increase the pH to 8-9. The solidprecipitate was filtered and washed with water and ethanol. The solidwas dried on the filter and in an oven. The product was14-hydroxycodeinone (150.52 g damp, 75.32 g dry weight, 75% yield).

The 14-hydroxycodeinone (39.45 g of the damp solid) was dissolved inwater (81.13 ml) and 80% acetic acid (16.17 ml). 10 wt % palladium oncarbon catalyst (0.33 g wet weight, 0.16 g dry weight) was added andhydrogen was passed through the mixture for about 6 hours at about 12psi. The mixture was filtered to remove the catalyst. An ammoniumhydroxide solution was added to the mixture up to pH 9. The solidprecipitate was washed with water and with ethanol, and was dried. Theproduct was oxycodone (18.8 g, 79% yield).

Comparative Example 1 Heating and Recrystallisation of Oxycodone

13.257 g of oxycodone prepared via Route A was added to a 250 ml flask.An ethanol/methanol mixture (70 ml) was added to the flask and themixture was stirred at room temperature, heated to reflux (78° C.) for 1hour, cooled to room temperature and then stirred at room temperature.The mixture was cooled in an ice bath for 30 minutes and the solidproduct was filtered and rinsed with an ethanol/methanol mixture. Thesolid was dried under vacuum for 3 hours. The product was oxycodone base(11.393 g, 85.95%) and contained 210 ppm of the α,β-unsaturated ketoneimpurity, 14-hydroxycodeinone.

Dissolving the oxycodone, heating to 78° C. for 1 hour andrecrystallising did not reduce the amount of 14-hydroxycodeinone in theoxycodone.

Comparative Example 2 Heating and Recrystallisation of Oxycodone

11 g of the oxycodone product from comparative example 1 was added to a250 ml flask. An ethanol/methanol mixture (55 ml) was added to the flaskand the mixture was stirred at room temperature, heated to reflux (78°C.) for 1 hour, cooled to room temperature and then stirred at roomtemperature. The mixture was cooled in an ice bath for 35 minutes andthe solid product was filtered and rinsed with an ethanol/methanolmixture. The solid was dried under vacuum overnight. The product wasoxycodone base (10.682 g, 97.1%) and contained 165 ppm of theα,β-unsaturated ketone impurity, 14-hydroxycodeinone.

A second step of dissolving the oxycodone, heating to 78° C. for 1 hourand recrystallising did not significantly reduce the amount of14-hydroxycodeinone in the oxycodone.

Example 1 Preparation of Oxycodone Hydrochloride Having Low Level ofImpurities

5 g of oxycodone product from comparative example 2 was added to a 100ml flask. Water (10 ml) and isopropanol (10 ml) were added and themixture was stirred. Concentrated hydrochloric acid (2.64 ml) was added.The mixture was heated to 75° C. for 10 hours and stirred at ambienttemperature overnight. The mixture was transferred to a hydrogenationbottle and was heated to 45° C. 5 wt % palladium on carbon catalyst (0.5g) was added to the mixture and hydrogen was passed through the mixtureat about 12 psi for 6.5 hours. The mixture was warmed to 55° C., passedthrough a filter paper, cooled to room temperature and then placed in anice bath for 30 minutes. The solid product was filtered, rinsed withcold isopropanol and dried overnight under a vacuum pump. The productwas oxycodone hydrochloride (5.533 g, 99.2%) and contained less than 2ppm 14-hydroxycodeinone (measured by HPLC and MS-SIM (mass spectrometrywith selected ion monitoring)).

Example 2a Preparation of Oxycodone Base Having Low Level of Impurities

1.2 g of crude oxycodone prepared via Route A was added to a 50 mlflask. Water (3.6 ml), isopropanol (3.6 ml) and formic acid (4.8 ml)were added. Concentrated hydrochloric acid (0.24 ml) was added. Themixture was heated to 75° C. and stirred at 75° C. for 10 hours. Themixture was cooled to room temperature and stirred. HPLC showed that thelevel of 14-hydroxycodeinone in the oxycodone increased during theheating step. Treatment with acid and heating does not prepare oxycodonewith a low level of impurities.

The mixture was transferred to a hydrogenation bottle. 5 wt % palladiumon carbon catalyst (120 mg) was added to the mixture and hydrogen waspassed through the mixture at room temperature and about 12 psi for 24hours. The mixture was passed through a pad of celite and then placed inan ice bath. 50% sodium hydroxide (5.3 ml) was added dropwise over 17minutes to a pH of 9-10. The mixture was stirred at 0-5° C. for 1 hourand 10 minutes. The solid product was filtered, rinsed with cold waterand dried under a vacuum pump for four hours. The product was oxycodonebase (1.072 g, 89.33%) and contained approximately 3 ppm14-hydroxycodeinone (measured by MS-SIM).

Example 2b Preparation of Oxycodone Hydrochloride Having Low Level ofImpurities

0.8 g of oxycodone base produced in Example 2a was added to a 50 mlflask. Water (1.6 ml) and isopropanol (3.76 ml) were added. Concentratedhydrochloric acid (0.32 ml) was added and the mixture was heated to 73°C. After 5 minutes at 73° C. the mixture was cooled to room temperatureand was then stirred at room temperature for 1 hour. The mixture wasplaced in an ice bath and stirred for 1.5 hours. The solid product wasfiltered, rinsed with cold isopropanol and dried under a vacuum pumpovernight. The product was oxycodone hydrochloride (0.892 g) andcontained approximately 5 ppm 14-hydroxycodeinone (measured by MS-SIM).

Example 3 Preparation of Oxycodone Hydrochloride Having Low Level ofImpurities

18.8 g oxycodone prepared via Route B was added to a flask containingethanol (43.9 ml) and water (10.14 ml). Ethanol (5.71 ml) andconcentrated hydrochloric acid (7.37 ml) were mixed and then added tothe flask, providing a mixture with a pH of 1. The mixture was heated at75° C. for 5 hours and was then cooled to 65° C. The mixture washydrogenated at 10-12 psi for six hours using a 10 wt % palladium oncarbon catalyst (175.6 mg wet weight, 88 mg dry weight). The mixture wasfiltered to remove the catalyst and cooled. The solid product wasfiltered and washed with ethanol. The product was oxycodonehydrochloride (20.13 g, 75.3%) and contained approximately 0 ppm14-hydroxycodeinone.

Comparative Example 3a Hydrogenation of Oxycodone

3 g of crude oxycodone prepared by essentially the same method as routeA and containing 535 ppm 14-hydroxycodeinone was added to ahydrogenation bottle. Isopropanol (9 ml), water (9 ml) and formic acid(12 ml) were added. The mixture was hydrogenated for 23 hours using a 5wt % palladium on carbon catalyst (0.3 g). The mixture was passedthrough a pad of celite and the hydrogenation bottle was rinsed withisopropanol and water. The mixture was cooled in an ice bath. 50% sodiumhydroxide (14 ml) was added dropwise over 22 minutes to a pH of 9-10.The mixture was stirred at 0-5° C. for 1 hour and 20 minutes. The solidproduct was filtered, rinsed with cold water and dried under a vacuumpump overnight. The product was oxycodone base (2.822 g, 94.1%) andcontained approximately 26 ppm 14-hydroxycodeinone (measured by HPLC).The hydrogenation step reduced the amount of 14-hydroxycodeinone in theoxycodone, but this method, wherein the pH of the mixture was notadjusted before the hydrogenation, did not afford oxycodone with animpurity level of less than 10 ppm.

Comparative Example 3b Acidification of Oxycodone

2 g of oxycodone base produced in Comparative Example 3a was added to a100 ml flask. Water (4 ml) and isopropanol (9.4 ml) were added.Concentrated hydrochloric acid (0.8 ml) was added and the mixture washeated to 70-72° C. After 5 minutes at 70-72° C. the mixture was slowlycooled to room temperature. The mixture was placed in an ice bath andstirred for 1 hour and 20 minutes. The solid product was filtered,rinsed with cold isopropanol and dried under a vacuum pump overnight.The product was oxycodone hydrochloride (2.401 g) and containedapproximately 38 ppm 14-hydroxycodeinone (measured by HPLC). Adjustingthe pH of the oxycodone to ˜1 and heating did not further reduce theconcentration of 14-hydroxycodone. Comparative Examples 3a and 3bdemonstrate that oxycodone with very low level of impurities (less than10 ppm 14-hydroxycodeinone) is not prepared by hydrogenating theoxycodone and then treating with acid.

Example 4 Preparation of Oxycodone Hydrochloride Having Low Level ofImpurities

4.35 g oxycodone prepared by essentially the same method as Route B wasadded to a flask containing ethanol (12.5 ml) and water (2.7 ml).Concentrated hydrochloric acid (approximately 1.5 ml) was added to theflask, providing a mixture with a pH of about 2. The pH of the mixturewas increased to 5 by adding ammonia. The mixture was hydrogenated at 45psi and 50° C. for 1.5 hours and then at 10-12 psi and 50-55° C. for 4hours using a 10 wt % palladium on carbon catalyst (0.06 g). The mixturewas filtered to remove the catalyst and cooled. The solid product wasfiltered and washed with ethanol. The product was oxycodonehydrochloride (3.706 g, 76.1%) and contained approximately 12 ppm14-hydroxycodeinone.

Example 5 Preparation of Oxycodone Hydrochloride Having Low Level ofImpurities

3 g of oxycodone product from comparative example 2 was added to a 50 mlflask. Water (1.3 ml) and ethanol (5.58 ml) were added and the mixturewas stirred. Concentrated hydrochloric acid (1.58 ml) was added. Furtherwater was added so that in total 4.5 ml of water was added. The mixturewas heated to 75° C. for 10 hours, slowly cooled to room temperature andstirred overnight. The mixture was heated to 40° C. and transferred to ahydrogenation bottle. 5 wt % palladium on carbon catalyst (0.3 g) wasadded to the mixture and hydrogen was passed through the mixture atbetween 11 and 12 psi for 6.5 hours. The mixture was warmed to 56° C.and passed through two layers of filter paper. The bottle and filtratewere rinsed with a hot solution of 1 ml water and 5 ml ethanol, and with20 ml of hot ethanol. The filtrate was slowly cooled to room temperatureand then placed in an ice bath for 30 minutes. The solid product wasfiltered, rinsed with cold ethanol and dried overnight under a vacuumpump. The product was oxycodone hydrochloride (2.663 g, 79.6% yield). Afurther 0.334 g of oxycodone hydrochloride was obtained by washing thefilter cake and hydrogenation bottle with water and water/ethanol (1:1),giving a combined yield of 2.997 g and 89.5%. Both samples of oxycodonehydrochloride contained 0 ppm 14-hydroxycodeinone (measured by HPLC andMS-SIM (mass spectrometry with selected ion monitoring)).

1. A method of purifying oxycodone or a salt thereof, comprising thesteps of: a) preparing a solution comprising the oxycodone or saltthereof in a solvent, said solution having a pH less than 6, and; b)maintaining the solution at a temperature of at least 55° C. for aperiod of at least 3 hours; wherein the step of maintaining is performedin the absence of hydrogenation reagents.
 2. The method of claim 1,wherein the oxycodone or salt thereof comprises oxycodone hydrochloride.3. The method of claim 1, wherein the pH is less than
 5. 4. The methodof claim 1, wherein the pH is less than
 3. 5. The method of claim 1,wherein the temperature is at least 60° C.
 6. The method of claim 1,wherein the temperature is from about 70° C. to 75° C.
 7. The method ofclaim 1, wherein the period is at least 5 hours.
 8. The method of claim1, wherein the period is from 5 to 10 hours.
 9. The method of claim 1,further comprising after step (b) the steps of: c) contacting thesolution with hydrogenation reagents for a period of at least 1 hour;and d) crystallizing the product of step (c) to form the purifiedoxycodone or salt thereof.
 10. The method of claim 9, wherein thepurified oxycodone or salt thereof is oxycodone hydrochloride.
 11. Themethod of claim 9, wherein the hydrogenation reagents comprise ahydrogenation catalyst and either hydrogen or a hydrogen transferreagent.
 12. The method of claim 1, wherein the pH is less than orabout
 1. 13. The method of claim 9, wherein the pH is less than orabout
 1. 14. The method of claim 9, wherein the purified oxycodone orsalt thereof comprises about 3 ppm of 14-hydroxycodeinone.
 15. Themethod of claim 9, wherein the purified oxycodone or salt thereofcomprises about 0 ppm of 14-hydroxycodeinone.
 16. The method of claim 1,further comprising, prior to preparing the solution, the steps ofwashing 14-hydroxycodeinone with ethanol and subsequently converting the14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone isthe oxycodone or oxycodone salt that is used for preparing the solution.17. The method of claim 1, further comprising, prior to preparing thesolution, the step of washing oxycodone with ethanol to form washedoxycodone and optionally forming a salt therefrom, wherein the washedoxycodone or salt formed therefrom is the oxycodone or oxycodone saltthat is used to prepare the solution.
 18. The method of claim 17,further comprising, prior to the step of washing the oxycodone, thesteps of washing 14-hydroxycodeinone with ethanol and subsequentlyconverting the 14-hydroxycodeinone to a crude oxycodone, wherein thecrude oxycodone is the oxycodone that is washed with ethanol.
 19. Themethod of claim 18, further comprising after step (b) the steps of: c)contacting the solution with hydrogenation reagents for a period of atleast 1 hour; and d) crystallizing the product of step (c) to form thepurified oxycodone or salt thereof; wherein the purified oxycodone orsalt thereof is oxycodone hydrochloride, the pH is less than or about 1,and step (b) is carried out for at least 5 hours at a temperature fromabout 70° C. to 75° C.
 20. The method of claim 19, wherein step (c) iscarried out for about 6 hours at a temperature from about 45° C. to 55°C.
 21. The method of claim 19, wherein step (b) is carried out for about10 hours at a temperature of about 75° C.
 22. The method of claim 11further comprising, after step (c), removing the hydrogenation catalystsby filtering to provide the product which is crystallized in step (d).23. The method of claim 1, further comprising after step (b) the stepsof: c) contacting the solution with hydrogenation reagents for a periodof at least 1 hour; and d) crystallizing the product of step (c) to formthe purified oxycodone or salt thereof; wherein the purified oxycodoneor salt thereof is oxycodone hydrochloride, the pH is less than or about1, and step (b) is carried out for at least 5 hours at a temperaturefrom about 70° C. to 75° C.
 24. The method of claim 23, wherein step (c)is carried out for about 6 hours at a temperature from about 45° C. to55° C.
 25. The method of claim 23, wherein step (b) is carried out forabout 10 hours at a temperature of about 75° C.